chr17-47284466-C-A

Position:

• chr17-47284466-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000212.3(ITGB3):​c.385C>A​(p.Gln129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 3.16

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ENSG00000259753 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB3	NM_000212.3	c.385C>A	p.Gln129Lys	missense_variant	4/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.385C>A	p.Gln129Lys	missense_variant	4/15	1	NM_000212.3	ENSP00000452786.2
ITGB3	ENST00000571680.1	c.385C>A	p.Gln129Lys	missense_variant	4/9	1		ENSP00000461626.1
ENSG00000259753	ENST00000560629.1	n.349C>A		non_coding_transcript_exon_variant	4/18	2		ENSP00000456711.2
ITGB3	ENST00000696963.1	c.385C>A	p.Gln129Lys	missense_variant	4/14			ENSP00000513002.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251468 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Mar 21, 2023

After a comprehensive literature search, the missense variant NM_000212.3:c.385C>A (p.Gln129Lys) was not identified in any individuals with Glanzmann thrombasthenia. The highest population minor allele frequency in gnomAD v2.1.1 is .00002 (2/113754 alleles) in the European (Non-Finnish) population (PM2_supporting). The computational predictor REVEL gives a score of 0.408, which is intermediate between PP3 and BP4. The variant was identified in relation to severe neonatal alloimmune thrombocytopenia, where the variant was found to have normal surface expression in HEK-293 cells, though this assay use did not meet our criteria for BS3 specification. In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive inheritance of Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2.1). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 129 of the ITGB3 protein (p.Gln129Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal alloimmune thrombocytopenia (PMID: 21896032). This variant is also known as p.Q103K. ClinVar contains an entry for this variant (Variation ID: 2498363). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGB3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ITGB3 function (PMID: 21896032). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Benign	0.83
DEOGEN2	Uncertain	0.50	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.050	N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.64	N;.
Sift	Benign	0.81	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.53
MutPred		0.49		Gain of methylation at Q129 (P = 0.0042);Gain of methylation at Q129 (P = 0.0042);
MVP		0.93
MPC		0.52
ClinPred		0.33	T
GERP RS		5.8
Varity_R		0.34
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281864909; hg19: chr17-45361832;